title: PI3Kδ drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation.
abstract: The Class IA phosphoinositide 3-kinase delta (PI3Kδ) has been implicated in multiple signaling pathways involved in leukocyte activation and hence is an attractive target in many human autoimmune diseases, including multiple sclerosis (MS). Here, using mice expressing a catalytically inactive form of the PI3Kδ subunit p110δ, we show that signaling through PI3Kδ is required for full and sustained pathology of experimental autoimmune encephalomyelitis (EAE), a Th17-driven model of MS. In p110δ-inactivated mice, T cell activation and function during EAE was markedly reduced and fewer T cells were observed in the central nervous system (CNS). The decrease in T cell activation is unlikely to be due to defects in dendritic cell (DC) function, as p110δ-inactivated DCs migrate and present antigen normally. However, significant increases in the proportion of T cells undergoing apoptosis at early stages of EAE were evident in the absence of PI3Kδ activity. Furthermore, a profound defect in Th17 cellular responses during EAE was apparent in the absence of PI3Kδ activity while Th1 responses were less affected. A highly selective PI3Kδ inhibitor, IC87114, also had greater inhibitory effects on Th17 cell generation in vitro than it did on Th1 cell generation. Thus, PI3Kδ plays an important role in Th17 responses in EAE, suggesting that small molecule inhibitors of PI3Kδ may be useful therapeutics for treatment of MS and other autoimmune diseases.
authors.affiliation: Chemokine Biology Group, School of Molecular & Biomedical Science, University of Adelaide, North Terrace Campus, Adelaide, South Australia 5005, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Haylock-Jacobs
authors.forename: Iain
authors.initials: I
authors.lastname: Comerford
authors.forename: Mark
authors.initials: M
authors.lastname: Bunting
authors.forename: Ervin
authors.initials: E
authors.lastname: Kara
authors.forename: Scott
authors.initials: S
authors.lastname: Townley
authors.forename: Manuela
authors.initials: M
authors.lastname: Klingler-Hoffmann
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D058534:Class I Phosphatidylinositol 3-Kinases; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000276:immunology; D005260:Female; D007156:Immunologic Memory; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C421683:Pik3cd protein, mouse